“Systemic Inflammatory Response Syndrome” (SIRS) occurs when the body's response to an insult is an uncontrolled, systemic inflammatory response. Death is caused by the exaggerated reaction rather than by the insult itself (Cohen, 2002). SIRS is diagnosed when the patient shows two or more of the following clinical findings: fever, increased heart or respiratory rate, and aberrant white blood cell count. SIRS can be caused by a sterile trigger, for instance, burns, hemorrhage, trauma, or by bacterial, viral or fungal infection. It is termed severe SIRS when there is organ failure, and if the patient has persistent hypotension despite fluid resuscitation, the condition is known as shock. In the presence of infection, it is known as sepsis, which can proceed to severe sepsis and septic shock.
SIRS remains one of the leading causes of death in intensive care units (ICUs) worldwide. About 750,000 cases of severe sepsis occur in the United States every year (Agnus et al., 2001) and this number will continue to rise as the population ages further and co-morbidities, such as, infarctions, alcohol abuse and obesity increase (Esper et al., 2006). One-fifth of patients in intensive care have sepsis, and mortality rate among severe sepsis patients is over 30% (Agnus et al., 2001).
Despite intensive research into SIRS pathology for the past decades, only a few new therapies have emerged, and current treatments remain mostly supportive. Treatments can aim to prevent infection or to treat it with antibiotics, and to cope with organ dysfunction and failure by supportive therapy, such as, fluid resuscitation, kidney dialysis, vasopressor administration and mechanical ventilation (van Ruler et al., 2009). Hardly any therapy deals with the host response, which is the underlying cause of the condition. The newest approved treatment strategy, the use of recombinant human activated protein C (Vincent, 2007), is subject to criticism. The lack of effective treatment, high prevalence rate, high mortality rate, high economic costs and rapidity by which antibiotics resistance develops all underscore the need for further extensive studies into SIRS pathology.
“Matrix Metallo-Proteinase” (MMP) activity was initially discovered in 1962 as a collagenolytic activity in the tail of tadpoles during the degradation of extracellular matrix (ECM) proteins, which is required for metamorphosis (Gross and Lapiere, 1962). To date, the MMP family comprises 25 structurally and functionally related members, of which 24 can be found in Mammals (Parks et al., 2004). MMPs are characterized by a shared multidomain structure, and in particular, a highly conserved catalytic domain consisting of a zinc (Zn2+)-binding consensus sequence. Another hallmark of MMPs is the activation of the inactive zymogen by the “cysteine switch,” which interrupts the interaction between a cysteine in the prodomain and the Zn2+ ion at the active site (Van Wart and Birkedal-Hansen, 1990). MMPs are important regulators of cellular activities: they collectively degrade all structural components of the ECM8 and thereby influence several physiological processes, including reproduction (Hulboy et al., 1997), embryogenesis (Vu and Werb, 2000), angiogenesis (Roy et al., 2006) and tissue remodeling (Page and McCaw, 2007). ECM degradation, besides facilitating cell migration, also leads to the release of bound signaling molecules, such as, chemokines, cytokines and growth factors. More recently, it has become widely agreed that MMPs also have a central role in the direct activation of signaling molecules, which proves that MMPs also contribute to various aspects of immunity (Cauwe et al., 2007). MMP activity is hardly detectable under normal physiological conditions, but it is evident during certain biological processes. Tight regulation occurs at the levels of transcription, activation of the zymogen, interaction with specific ECM components, and inhibition by endogenous inhibitors (Sternlight and Werb, 2001). Breakdown of the regulation of MMP activity could lead to diseases, such as, arthritis, tumor metastasis and fibrosis (Malemud, 2006).
Matrix metalloproteinase-8 (MMP8), also known as collagenase-2 or neutrophil collagenase, was originally believed to be expressed only by neutrophils. More recently, it has become clear that MMP8 can be expressed in a wide range of cells, such as, epithelial cells, fibroblasts and macrophages, mainly during inflammatory conditions (Van Lint and Libert, 2006). Inactive MMP8 is stored in the intracellular granules of neutrophils and is released upon activation to ensure rapid availability of MMP8 at inflammatory sites. The effect of MMP8 expression on cancer progression and its association with several inflammatory disorders has been described (Van Lint and Libert, 2006). Tester et al., (2007) described that MMP8−/− mice are no longer LPS responsive. As a consequence, MMP inhibitors in general, and MMP8 inhibitors particularly are claimed in the treatment of, amongst other, inflammation. WO9633172 discloses the use of arylsulfonyl hydroxamic derivatives as MMP inhibitors, and their use for treatment of sepsis and septic shock. U.S. Pat. No. 6,686,355 discloses the use of MMP inhibiting biphenyl sulfonamide derivatives to treat inflammation. WO0162261 describes the use of tetracycline based antibiotics to inhibit MMP1 , MMP2 , MMP8 or MMP9 in respiratory diseases. Small compound inhibitors, however, have the disadvantage to be cross reactive with several MMP's thereby causing unwanted side effects. Therefore, several researches tried to develop more specific inhibitors, including inactivating antibodies. Whereas several MMP specific antibodies have been described for detection and immunological staining of MMP's only few antibodies have been described with MMP inactivating activity, and no inactivating MMP8 antibody has been described.